Chemoselective Difluoromethylation of Nucleosides

Abstract

A profiling platform to define the chemoselectivity of the carbene-mediated difluoromethylation of nucleosides is described. First, the optimized reaction conditions for the difluoromethylation of silyl-protected nucleosides are established using TMS-CF₂Br and KOAc to form the difluoromethyl carbene in situ. Second, the scope of these reaction conditions to difluoromethylate uridine- and cytidine-based 2'-deoxyribonucleoside and ribonucleoside analogues is established. When uridine analogues are substrates, O-difluoromethylation at the 4-position is observed, whereas O-difluoromethylation at the 2-position of cytidine analogues predominates. S-Difluoromethylation is preferable over O-difluoromethylation when thionucleosides are used. In all cases, no N-difluoromethylation is observed. Finally, silyl deprotection afforded difluoromethylated free nucleosides, thereby enabling the exploration of their utility for broader applications in medicinal chemistry and chemical biology.

1

(A) Representative therapeutic fluorinated nucleosides. (B) Difluoromethylation of heterocycles via formation of difluorocarbene in situ. (C) Chemoselectivity reaction profiling platform for late-stage nucleoside difluoromethylation (this work).

2

(A) 3′/5′-Silyl-protected nucleoside substrates used to explore chemoselective difluoromethylation. (B) Difluoromethylated nucleoside products.

3

(A) Uridine substrates used to explore the chemoselectivity of the nucleobase and (B) difluoromethylated products. ^a Yield of the 1 mmol scale reaction. (C) Cytidine substrates used to explore the chemoselectivity of the nucleobase and (D) difluoromethylated products. ^b Conversion to the crude product after 1 h.

1. (A) Optimization of the Silyl Deprotection Condition to Form Nucleoside 40, Where (a) Denotes Partial Hydrolysis of the Difluoromethyl Group, (b) Denotes Incomplete Deprotection, and (c) Denotes Isolation of the Product as a Salt, and (B) Scope of the Silyl Deprotection Condition

2. (A) Optimization of the Silyl Deprotection Condition to Form Nucleoside 43 and (B) Scope of the Silyl Deprotection Condition, Where (a) Denotes Partial Hydrolysis of the Difluoromethyl Group and (b) Denotes Incomplete Deprotection

3. Reaction Conditions for Telescoped Reaction Series